Interleukin-4 Modulates the Inflammatory Response in Ifosfamide-Induced Hemorrhagic Cystitis
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Interleukin-4 Modulates the Inflammatory Response in Ifosfamide-Induced Hemorrhagic Cystitis Francisco Yuri Bulcão Macedo,1 Lívia Talita Cajaseiras Mourão,1 Helano Carioca Freitas,1 Roberto C. P. Lima-Júnior,1 Deysi Viviana Tenazoa Wong,1 Reinaldo Barreto Oriá,2 Mariana L. Vale,1 Gerly Anne Casto Brito,2 Fernando Q. Cunha,3 and Ronaldo A. Ribeiro1,4,5
Abstract—We investigated whether interleukin-4 (IL-4) is present and capable of reducing inflammatory changes seen in ifosfamide-induced hemorrhagic cystitis. Male Swiss mice were treated with saline or ifosfamide alone or ifosfamide with the classical protocol with mesna and analyzed by changes in bladder wet weight (BWW), macroscopic and microscopic parameters, exudate, and hemoglobin quantification. In other groups, IL-4 was administered intraperitoneally 1 h before ifosfamide. In other experimental groups, C57BL/6 WT (wild type) and C57BL/6 WT IL-4 (−/−) knockout animals were treated with ifosfamide and analyzed for changes in BWW. Quantification of bladder IL-4 protein by ELISA in control, ifosfamide-, and mesna-treated groups was performed. Immunohistochemistry to tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) as well as protein identification by Western blot assay for inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was carried out on ifosfamide- and IL-4-treated animals. In other experimental groups, antiserum against IL-4 was given 30 min before ifosfamide. In IL-4-treated animals, the severity of hemorrhagic cystitis was significantly milder than in animals treated with ifosfamide only, an effect that was reverted with serum anti-IL-4. Moreover, knockout animals for IL-4 (−/−) exhibit a worse degree of inflammation when compared to C57BL/6 wild type. Exogenous IL-4 also attenuated TNF-α, IL-1β, iNOS, and COX-2 expressions in ifosfamide-treated bladders. IL-4, an anti-inflammatory cytokine, attenuates the inflammation seen in ifosfamide-induced hemorrhagic cystitis. KEY WORDS: IL-4; ifosfamide; bladder; hemorrhagic cystitis; TNF-α; IL-1β; iNOS; COX-2.
for malignant lymphomas and non-Hodgkin’s lymphoma. Also, it can be given for the treatment of refractory tumors that do not respond to conventional therapy, such as soft tissue sarcoma and refractory germ cell tumors [1]. Within the liver, ifosfamide is cleaved into its active compound isofosforamide mustard, and acrolein, an inactive metabolite excreted by the urinary system [2]. Hemorrhagic cystitis (HC) is a complication that limits the use of ifosfamide. It has been proposed that such toxicity is attributable to the renal excretion of acrolein. Urothelial damage occurs upon direct contact with acrolein, which causes edema, ulceration, neovascularization, hemorrhage, necrosis, and expression of inflammatory enzymes [3]. Prophylactic mesna (2-mercaptoethanesulfonic acid) has shown some efficacy in becoming the drug of
INTRODUCTION Ifosfamide is a chemotherapeutic agent primarily indicated in some hematological conditions such as chronic lymphocytic leukemia and as adjunctive thera
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